Drug delivery product for controlled drug delivery

ABSTRACT

Present invention provides fully or partially biodegradable drug delivery product for controlled delivery of drugs. In one embodiment, the present invention relates to a drug delivery product having a shell comprising a first material and a second material, wherein the second material comprises a first biodegradable material; a core comprising a drug, the core being enclosed by the shell; wherein the first material is distributed in a matrix of the first biodegradable material; wherein the first material is configured to create holes in the shell; wherein the holes allow the drug to be released to the exterior of the shell through the holes.

RELATED APPLICATIONS

The present application is a division of U.S. application Ser. No.15/011,181, entitled ““FULLY OR PARTIALLY BIODEGRADABLE DEVICE FORCONTROLLED DRUG DELIVERY,” filed on Jan. 29, 2016, which claims benefitfrom U.S. Provisional Application 62/109,391, entitled “FULLY ORPARTIALLY BIODEGRADABLE DEVICE FOR CONTROLLED DRUG DELIVERY,” filed onJan. 29, 2015; all of the above applications are incorporated herein byreference in their entirety.

The present invention is related U.S. Patent Publications: (1) US20140056962 entitled “DRUG DELIVERY SYSTEM;” (2) US 20130115265 entitled“DRUG DELIVERY SYSTEM;” (3) US 20130078286 entitled “DRUG DELIVERYSYSTEM;” (4) US 20120058171 entitled “ZOO-TECHNICAL DRUG DELIVERYDEVICE;” (5) US 20120052108 entitled “MACROCYCLIC LACTONE DRUG DELIVERYSYSTEM;” (6) US 20100203104 entitled “DELIVERY SYSTEM FOR RISPERIDONE;”(7) US 20100129425 entitled “VAGINAL DELIVERY SYSTEM FOR MIRTAZAPINE;”(8) US 20100104619 entitled “DELIVERY SYSTEM FOR A NON-STEROIDALNON-IONIZED HYDROPHILIC DRUG;” (9) US 20090081278 entitled “DrugDelivery System;” (10) US 20080112892 entitled “X-Ray Visible DrugDelivery Device;” (11) US 20070141102 entitled “Drug delivery systembased on polyethylene vinylacetate copolymers;” (12) US 20060280771entitled “Drug delivery system;” (13) US 20130280334 entitled“Nanostructured Gels Capable of Controlled Release of EncapsulatedAgents;” (14) US 20100129459 entitled “Biodegradable microspherecomposition suitable for the controlled release of glucose controllingpeptide and formulation thereof.” All U.S. patents and U.S. patentPublications referred above and in the application are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

The present invention is related to a biodegradable device forcontrolled delivery of drugs. The device comprises micro/nano fluidicbeads containing a drug embedded in a biodegradable polymer matrix, suchas biodegradable foam, further enclosed by a skin or barrier layer thatprevents entry of blood cells into the biodegradable foam whilepermitting entry of blood serum. The device is supplied with anapplicator for drug delivery. The invention also relates to a method ofadministering the device to a patient in need thereof and use of thedevice for delivering a variety of drugs including small molecules tobiologicals.

BACKGROUND OF THE INVENTION

Implantable device systems for controlled delivery of drugs have longbeen explored especially for chronic therapies. Treatment for chronicailments requires multiple administration of a drug over a long periodof time. Sustained delivery is highly desirable for delivery ofbioactive agents particularly biologicals like peptides, antibodies andnucleic acid analogs. This kind of delivery would provide optimumtherapeutic efficacy with minimum side effects and thereby improvepatient compliance.

More preferably the implantable device therapeutic systems are builtfrom bioabsorbable material. These therapeutic systems deliver theactive to an in vivo patient site and can occupy that site for extendedperiods of time without being harmful to the host.

Various approaches for preparing bioabsorbable drug delivery systemshave been reported in literature. U.S. Patent Application PublicationsUS 2005/0043816 and US2007/0190108, U.S. Pat. No. 5,522,895 (Mikos),U.S. Pat. No. 5,514,378 (Mikos et al.), U.S. Pat. No. 5,133,755(Brekke), U.S. Pat. No. 5,716,413 (Walter et al.), U.S. Pat. No.5,607,474 (Athanasiou et al.), U.S. Pat. No. 6,306,424 (Vyakarnam et.al), U.S. Pat. No. 6,355,699 (Vyakarnam et. al), U.S. Pat. No. 5,677,355(Shalaby et al.), U.S. Pat. No. 5,770,193 (Vacanti et al.), and U.S.Pat. No. 5,769,899 (Schwartz et al.). covers bioabsorbable deliverytissue substrate that serves as a scaffold or support onto which cellsmay attach.

The major weaknesses of these approaches relating to bioabsorbablethree-dimensional porous scaffolds used for tissue regeneration areundesirable tissue response during the product's life cycle as thepolymers biodegrade and the inability to degrade adequately in vivo,thus severely limiting their ability to serve as effective scaffolds.

US20140046255 relates to a methods and apparatus for a free-standingbiodegradable patch suitable for intravascular application comprising afree-standing film or device having a mixture of a solid fibrinogencomponent and a solid thrombin component that, when exposed to anaqueous environment, undergoes polymerization to form fibrin.

Present invention has a valuable contribution in a state of art sincethe invention provides a delivery device that is biodegradable,withstands mechanical force by e.g. catheter, endoscope, arthoscope, orsyringe during delivery to a biological site, but is capable ofexpansion by resiliently recovery to occupy and remain in the biologicalsite.

SUMMARY OF THE INVENTION

Present invention provides fully or partially biodegradable device forcontrolled delivery of drugs.

In one embodiment, the present invention relates provides biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix.

In one embodiment, the present invention relates provides biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, e.g., a biodegradable sol-gel orbiodegradable thermoplastic polymer, further comprising a biodegradablefoam. In one aspect, the biodegradable foam is present inside thepolymer matrix. In another aspect, the biodegradable foam is at leastpartially coated on the polymer matrix. In yet another aspect, thebiodegradable foam is completely coated on the polymer matrix.

In one embodiment, the present invention relates to biodegradable devicefor controlled delivery of drugs, comprising a micro or nano fluidicbeads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, further comprising a biodegradable foam.The biodegradable foam and/or the skin or barrier layer has a definedpore size such that physical movement of a droplet is restrained andfree flow through serum but not through blood cells.

In one aspect of this embodiment, the pore size in the barrier layer isless than about 10 micron. Preferably the pore size is less than about 5micron.

In one embodiment, the present invention relates to biodegradable devicefor controlled delivery of drugs, comprising a micro or nano fluidicbeads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, further comprising a biodegradable foam,wherein the device can be implanted into specific organs or underneaththe skin for an effective local or systemic delivery of drug.

In one embodiment, the present invention relates to biodegradable devicefor controlled delivery of drugs, comprising a micro or nano fluidicbeads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, further comprising a biodegradable foam,wherein the device is completely biodegradable such that it degrades inthe body without a need for removal of the implant.

In one embodiment, the present invention relates to biodegradable devicefor controlled delivery of drugs, comprising a micro or nano fluidicbeads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, further comprising a biodegradable foam,wherein the device provide sustained drug delivery for a prolongedperiod of tile. Preferably, the time period of ranges from about 1 weekto about 5 years. More preferably, the time period of ranges from about1 month to about 3 years.

The biodegradable device of the present invention is advantageous overtransdermal patches. The transdermal drug delivery system has severallimitations since skin forms a very effective barrier and thus thesystem is suitable for the only medications that have small enough sizeto penetrate the skin such as molecules having molecular weight lessthan 500. Further, molecule with sufficient aqueous and lipidsolubility, having an octanol/water partition coefficient (log P)between 1 and 3 is required for permeate to transverse subcutaneous andunderlying aqueous layers. Patches are known to have side effects likeerythema, itching, local edema and allergic reaction can be caused bythe drug, the adhesive, or other excipients in the patch formulation.Also “dose dumping is one of the serious implications of patch. In oneembodiment, the biodegradable device of the present invention overcomesthese limitations of transdermal patch.

In one embodiment, the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix further comprising a biodegradable foam,wherein the matrix comprises an elongated shape, such as the shapes ofcylinders, rods, tubes or elongated prismatic forms, or a folded,coiled, helical or other more compact configuration such as cubes,pyramids, tetrahedrons, cones, cylinders, trapezoids, parallelepipeds,ellipsoids, fusiforms, tubes or sleeves. A dimension of the matrixranges from about 0.5 millimeter to about 5 centimeter. In a preferredaspect of embodiment, the matrix comprises single rod shaped implanthaving a length of about 4 centimeter and diameter of about 2millimeter.

In one aspect of this embodiment, the biodegradable device is pre-loadedin a needle supplied with s disposable applicator.

In one embodiment, the present invention relates to a method ofadministering the biodegradable device for controlled delivery of drugs,comprising a micro or nano fluidic beads that contains drug, wherein thebeads are embedded in a biodegradable polymer matrix, further comprisinga biodegradable foam.

In one embodiment, the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix further comprising biodegradable foamwherein the biodegradable polymer matrix comprising a biocompatible,cross-linked, biodegradable polyurethane, the matrix having acontinuous-interconnected void phase. According to an aspect, thepolyurethane degrades in a body of an animal to cause a loss of weightof the matrix and the resultant void phase is further ingrown andproliferated by tissues or biological tissue and in one embodiment,further ingrown and proliferated tissues can re-model to becomesubstantially similar to the surrounding tissue in the body of an animalwhere it was placed.

In one embodiment, the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix further comprising a biodegradable foam,wherein the device is suitable for delivery of small molecules havingmolecular weight less than 500 as well as large biologics entities likepeptides, antibodies and nucleic acid analogs such as modified RNA,small interfering RNA, anti-sense DNA or fragments thereof.

In one embodiment, the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix further comprising a biodegradable foam,wherein the device is suitable for delivery of lidocaine, diclofenec,clonidine, estradiol, estradiol/norethindrone acetate,estradiol/levonorgestrel, fentanyl, methylphenidate, nicotine,norelgestromin/ethinyl estradiol, nitroglycerin, oxybutynin,scopolamine, selegiline, testosterone, rivastigmine, rotogotine.

In one embodiment, the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix further comprising a biodegradable foam,wherein the device is suitable for delivery of long-term sustainedrelease of insulin or analogs thereof, GLP-1 or analogs thereof, aloneor in combination of other therapies, to treat diabetes or othermetabolic conditions.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of long-term release of contraceptive hormones, combinationof estrogen or progestin or singular delivery of progesterone alone andserves as contraceptive aid for women.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of long-term therapeutic benefit for ocular diseases, suchas age related macular degeneration, dry eye and various others.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of any small molecule or biologic therapy to treat urinarybladder complications such as incontinence, yeast infections, bladdercancer and various others.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of therapeutic molecules to the male reproductive organs asa means to treat medical conditions such as erectile dysfunction,premature ejaculation, testicular cancer and various others pertainingto male reproductive system.

In one aspect of this embodiment the biodegradable device is suitablefor delivery of therapeutic molecules to female reproductive organs,uterus and ovaries, to treat medical conditions such as endometriosis,uterine fibroids, ovarian cancer, uterine cancer, poly cystic ovariansyndrome, and various other diseases pertaining to female reproductivesystem.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of therapeutic molecules to heart to treat conditions suchas heart failure, myocardial ischemia, and various other heart diseases.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of therapeutic molecules into the adipose tissue to treatconditions such as metabolic syndrome, diabetes, hypercholesterolemia,hypertriglyceridemia and various others.

In another embodiment, the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, further comprising a biodegradable foamwherein a top coating can be applied to delay release of the activeagent. In another embodiment, a top coating can be used as the matrixfor the delivery of a second active agent. A layered coating, comprisingrespective layers of fast- and slow-hydrolyzing polymer, can be used tostage release of the active agent or to control release of differentactive agents placed in the different layers. Polymer blends may also beused to control the release rate of different active agents or toprovide a desirable balance of coating characteristics (e.g.,elasticity, toughness) and drug delivery characteristics (e.g., releaseprofile). Polymers with differing solvent solubilities can be used tobuild-up different polymer layers that may be used to deliver differentactive agents or to control the release profile of a active agents.

The amount of an active agent present depends upon the particular theactive agent employed and medical condition being treated. In oneembodiment, the active agent is present in an effective amount. Inanother embodiment, the amount of the active agent represents from about0.01% to about 60% of the coating by weight. In another embodiment, theamount of the active agent represents from about 0.01% to about 40% ofthe coating by weight. In another embodiment, the amount of the activeagent represents from about 0.1% to about 20% of the coating by weight.

Another embodiment relates to a device comprising a shell comprising afirst material and a second material, wherein the second materialcomprises a biodegradable material; a core comprising a pharmaceuticallyeffective composition, the core being enclosed by the shell; wherein thefirst material is distributed in a matrix of the biodegradable material;wherein the first material is configured to create holes in the shell;wherein the holes allow the pharmaceutically effective composition to bereleased to the exterior of the shell through the holes. In oneembodiment, the shell could be made by polymerizing asilica-functionalized monomer to form a silica-containing biodegradablepolymer shell.

Preferably, the first material comprises a metal-containing materialthat can be heated to form the holes or a biodegradable material thatdegrades over time. Preferably, the metal-containing material ifconfigured to be heated under radiation, before or after implanting orattaching the device in or on a body of a human or an animal, to formthe holes. Preferably, the metal-containing material comprises metallicparticles. Preferably, the metallic component comprises aniron-containing material or an iron-containing polymer. Preferably, themetallic particles comprise iron-containing particles or aniron-containing polymer. Preferably, the first material comprises abiodegradable material. Preferably, the first and second materialscomprise polymers. Preferably, the first material comprises poly lactidacid (PLA) or an iron-containing polymer and the second biodegradablematerial comprises poly ε-caprolactone (PCL). Preferably, the corecomprises an emulsion or beads of the pharmaceutically effectivecomposition and a polymer.

Preferably, the pharmaceutically effective composition comprises atargeting material or targeting molecule that binds to a certain organ,object or a specific site within a body of a human or an animal.

DESCRIPTION OF FIGURES

FIG. 1: Biodegradable device comprising a micro or nano fluidic beadsthat contains drug, wherein the beads are embedded in a biodegradablepolymer matrix, further comprising a biodegradable foam.

FIG. 2: Biodegradable reticulated foam formed after thermal reticulationwherein the boundary skin layer formed during the foaming process wastrimmed and removed prior to subjecting the as-made foam to thermalreticulation.

FIG. 3: Biodegradable device comprising a micro or nano fluidic beadsthat contains drug, wherein the beads are embedded in a biodegradablepolymer matrix, further coated with a biodegradable foam.

FIG. 4: Biodegradable device along with its applicator.

DETAILED DESCRIPTION OF THE INVENTION

Present invention provides biodegradable device for controlled deliveryof drugs.

“Drug” in context of the present invention may include a small moleculetherapeutic active agent, a biological active agent. The terms drug,active, active agent, therapeutic agent are used interchangeably.

In one embodiment, the present invention relates provides biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix.

“Micro or nano beads” or “micro or nano fluidic beads” in context of thepresent invention have an ability to release a drug in a controlledmanner and comprises of micro droplet embedded or floating in a naturalfoam and surrounded by a biodegradable mesh made of natural material ora biodegradable polymer. The beads may be spherical or substantiallyspherical in shape, having its largest transverse dimension isequivalent to the diameter of the bead. Alternatively the bead may benon-spherical, for example, ellipsoidal or tetrahedral in shape havingits largest transverse dimension is equivalent to the greatest distancewithin the bead from one bead surface to another e.g., the major axislength for an ellipsoidal bead or the length of the longest side for atetrahedral bead.

The embodiments herein describes a drug delivery system a combination,comprising of a core comprising micro/nano-fluidic beads that containsthe active pharmaceutical or biologic agent with an ability to releasethe drug in a controlled release fashion. The core could be surroundedby a biodegradable mesh or patch with a defined pore size of less than10 micron, preferably less than 5 microns, to restrain the physicalmovement of the droplet but to allow the free flow of serum but notblood cells from accessing the core droplet. The core could also besurrounded by a biodegradable barrier such as a biodegradable polymerskin layer having channels of less than 5 micron width. The channelscould run from one end of the core to the other end of the core, if thecore is shaped like a cylinder, for example. The channels could runstraight from one end of the core to the other end of the core or theycould run in a spiral fashion.

The time for biodegradability of the beads (t₁) is shorter than the timefor biodegradability of foam or polymer matrix (t₂) in which the beadsare embedded, and in turn the time for biodegradability of the foam orpolymer matrix is shorter than the time for biodegradability of the skinlayer (t₃), such as mesh, or a barrier layer surrounding the foam orpolymer matrix. Applying these time scales (t₁<t₂<t₃) for thebiodegradability of the different components of the drug delivery deviceof the embodiments herein, even when the foam degraded it would notcause an individual to have any hypersensitive reaction from thedegradation of the foam as the degraded foam products would remainenclosed within the skin or barrier layer, which would degrade the last.In one embodiment, t₁<t₂<t₃, for example, could be 1-3 months, 3-6months and 6-12 months, respectively.

Yet in another embodiment, the core could be surrounded by abiodegradable barrier such as a biodegradable polymer skin layercomprising a biodegradable polymer that swells and creates openingsthrough biodegradable polymer skin layer, wherein the openings are largeenough to allow the drug to leach out of the core into the body of ahuman or animal into which the drug delivery device is implanted.

In yet another embodiment, the biodegradable foam of the core could beopen cell biodegradable foam and the drug containing beads fixed to thewalls of the open cell biodegradable foam. For example, the open cellbiodegradable foam could have an average cell size of about 300 micronwith openings between adjacent cells of about 200 micron, and thediameter of drug containing beads could be about 40 micron, with thebead wall having a thickness of 1-20 micron to allow beads to rupture atdifferent times within the body of a human or animal into which the drugdelivery device is implanted. The beads could be bonded to the walls ofthe open cell biodegradable foam by coating the beads with a coatinglayer that functions as an adhesive between the beads and the cellwalls. Alternatively, the coating layer can be crosslinked so as to forma bond, such as a covalent bond, between the beads and the cell wells.

The open cell biodegradable foam could be reticulated foam formed afterthermal reticulation such those disclosed in U.S. Pat. No. 8,801,801,entitled “AT LEAST PARTIALLY RESORBABLE RETICULATED ELASTOMERIC MATRIXELEMENTS AND METHODS OF MAKING SAME,” which is incorporated herein inits entirety. In the biodegradable reticulated foam, the boundary skinlayer formed during the foaming process was trimmed and removed prior tosubjecting the as-made foam to thermal reticulation. The open cellbiodegradable foam in the embodiments herein is generally resilient tocrushing when implanted within the body of a human or animal; therebythe open cell biodegradable foam substantially maintains its originalshape before implantation even after implantation within the body of thehuman or animal.

In yet another embodiment, the biodegradable foam could be closed cellbiodegradable foam formed by bonding together a plurality of drugcontaining beads. The diameter of drug containing beads could be about40 micron, with the bead wall having a thickness in the range of 1-20micron to allow beads to rupture at different times within the body of ahuman or animal into which the drug delivery device is implanted.

In yet another embodiment, the biodegradable device for controlleddelivery of drugs comprises of three regions: (1) a core, (2) anintermediate layer and (3) an outer skin or barrier layer. The core isan inner structure within the intermediate layer. The core may or maynot include the drug containing beads. In case the core contains thedrug containing beads, the intermediate layer could contain anadditional drug or a material that regulates the flow of the drugreleased from the core into the patient. In case the core does notcontain the drug containing beads, the intermediate layer contains thedrug containing beads; it is the compartment which contains the drug tobe delivered to the patient and is covered by the skin layer. The corecould comprise a biodegradable foam. The intermediate layer surroundingthe core could be formed of a biodegradable polymer. The core can alsocontribute to the strength or flexibility of the device and to increasedrug substance efficiency.

The drug delivery device of the embodiments herein can be implanted intospecific organs, such as vagina, or underneath the skin for an effectivelocal or systemic delivery of the pharmaceutical agent. In oneembodiment, the present invention relates provides biodegradable devicefor controlled delivery of drugs, comprising a micro or nano fluidicbeads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, further comprising biodegradable foam. Inone aspect, the biodegradable foam is present inside the polymer matrix.In another aspect, the biodegradable foam is at least partially coatedon the polymer matrix. In yet another aspect, the biodegradable foam iscompletely coated on the polymer matrix.

In one embodiment, the present invention relates to biodegradable devicefor controlled delivery of drugs, comprising a micro or nano fluidicbeads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, further comprising biodegradable foam. Thebiodegradable foam and/or the skin or barrier layer has a defined poresize such that physical movement of a droplet is restrained and freeflow through serum but not through blood cells.

In one embodiment, the present invention relates to biodegradable devicefor controlled delivery of drugs, comprising a micro or nano fluidicbeads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, further comprising a biodegradable foam,wherein the device can be implanted into specific organs or underneaththe skin for an effective local or systemic delivery of drug.

In one embodiment, the present invention relates to biodegradable devicefor controlled delivery of drugs, comprising a micro or nano fluidicbeads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, further comprising a biodegradable foam,wherein the device is completely biodegradable such that it degrades inthe body without a need for removal of the implant.

In one embodiment, the present invention relates to biodegradable devicefor controlled delivery of drugs, comprising a micro or nano fluidicbeads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, further comprising a biodegradable foam,wherein the device provide sustained drug delivery for a prolongedperiod of tile. Preferably, the time period of ranges from about 1 weekto about 5 years. More preferably, the time period of ranges from about1 month to about 3 years.

The beads used in the drug delivery device of the embodiments herein canbe made by microfluidics. Microfluidics-based technology enables precisecontrol and manipulation of fluids constrained to micron-sizedcapillaries. Advantages of microfluidics include reduced sample size andreagent consumption, short processing times, enhanced sensitivity,real-time analysis, and automation. More specifically, drop-basedmicrofluidics allows for the creation of micron-sized emulsions that canhold discrete picoliter volumes, with drop-making frequencies of greaterthan 2,000 drops per second (2 kHz).

Soft lithography techniques could be employed to fabricate microfluidicdevices for bead fabrication. For example, in one embodiment, AutoCADsoftware was used to generate a UV photomask containing micron-sizedcapillaries of desired structure and dimension. A silicon wafer wascoated with UV photoresist, on which the photomask was placed. After UVexposure, the silicon wafer was developed with propylene glycolmonomethyl ether acetate (PGMEA) to generate a positive resist with thedesired channels exposed. Polydimethylsiloxane (PDMS) was poured atopthe positive resist and incubated at 65° C. overnight. After removingthe PDMS (now a negative resist with the desired channels) from thesilicon wafer, the inlets were punched and the PDMS was bonded to glassvia plasma-activated bonding. The devices were treated with hydrophobicAquapel to prevent the wetting of channels during drop formation. Thedevice for droplet formation is disclosed in U.S. Patent Publication20120222748, entitled “DROPLET CREATION TECHNIQUES,” which isincorporated herein by reference in its entirety.

Additional U.S. patents and Publications related to droplet formationand are incorporated herein by reference in their entirety are:

(1) U.S. Pat. No. 7,776,927 B2—This is a patent broadly describesmethods of droplet generation and describes some potential uses in drugdelivery.

(2) US20120141589 A1—This patent describes some compounds (such asCaCO₃) with which the microfluidic emulsions could be made withdepending on the drug encapsulated in the emulsion, droplets and beads.

(3) US20130202657—This publication describes a microfoam for drugdelivery. Such a microfoam could be incorporated as the foam or mesh inthe drug delivery device of the embodiments herein.

(4) U.S. Pat. No. 6,858,220 B2—This patent discloses an implantablebiocompatible microfluidic drug delivery system using only channels, butnot microbeads containing a drug.

(5) US20130035574, US20130035660—These publications describe the actualchip/patch rather than the microbeads. However, the publications usemicrofluidics as well as scaffolding for drug delivery.

(6) U.S. Pat. No. 7,560,036 B2—This patent describes in detail thefabrication of the surface substrate, and uses microneedles for drugdelivery.

The drug containing beads could be made from droplets, for example,formed in accordance with the droplet creation techniques disclosed inU.S. Patent Publication US20120222748, for the drug delivery device ofthe embodiments by crosslinking biodegradable polymer of the shell ofthe drug containing beads. The crosslinking density of the biodegradablepolymer of the shell could be varied such that even for the same shellthickness, the drug containing beads with low crosslinking density wouldrupture at earlier time than the drug containing beads with highcrosslinking density when the drug containing beads are exposed to bloodserum or any other bodily fluid, for example.

The drug containing beads in the embodiments herein can be sustainedrelease particles having an inner core, which could be hollow or solidor porous, containing an active pharmaceutical ingredient, an optionalintermediate coating substantially surrounding the inner core, and anouter coating substantially surrounding the optional intermediatecoating comprising a pH independent polymer such as that disclosed inU.S. Patent Publication 20080187579, entitled “Extended-release dosageform,” which is incorporated herein in its entirety. The drug deliverydevice of the embodiments herein could have two or more bead populationswherein each of the bead populations has a different drug releaseprofile. The method of preparing an extended release dosage compositioncomprising one or more bead populations could be that disclosed in U.S.Patent Publication 20080187579, with an additional requirement that thebeads are made of biodegradable material such as a biodegradablepolymer.

The biodegradable device of the present invention is advantageous overtransdermal patches. The transdermal drug delivery system has severallimitations since skin forms a very effective barrier and thus thesystem is suitable for the only medications that have small enough sizeto penetrate the skin such as molecules having molecular weight lessthan 500. Further, molecule with sufficient aqueous and lipidsolubility, having a octanol/water partition coefficient (log P) between1 and 3 is required for permeate to transverse subcutaneous andunderlying aqueous layers. Patches are known to have side effects likeerythema, itching, local edema and allergic reaction can be caused bythe drug, the adhesive, or other excipients in the patch formulation.Also “dose dumping is one of the serious implications of patch. In oneembodiment, the biodegradable device of the present invention overcomesthese limitations of transdermal patch.

In one embodiment, the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix further comprising a biodegradable foam,wherein the matrix comprises an elongated shape, such as the shapes ofcylinders, rods, tubes or elongated prismatic forms, or a folded,coiled, helical or other more compact configuration such as cubes,pyramids, tetrahedrons, cones, cylinders, trapezoids, parallelepipeds,ellipsoids, fusiforms, tubes or sleeves. A dimension of the matrixranges from about 0.5 millimeter to about 5 centimeter. In a preferredaspect of embodiment, the matrix comprises a single rod shaped implanthaving a length of about 4 centimeter and diameter of about 2millimeter.

In one aspect of this embodiment, the biodegradable device is preloadedin a needle supplied with s disposable applicator.

In one embodiment the present invention relates to a method ofadministering the biodegradable device for controlled delivery of drugs,comprising a micro or nano fluidic beads that contains drug, wherein thebeads are embedded in a biodegradable polymer matrix, further comprisinga biodegradable foam.

In one embodiment, the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix further comprising a biodegradable foamwherein the biodegradable polymer matrix comprising a biocompatible,cross-linked, biodegradable material, collagen, fibronectin, elastin,hyaluronic acid or a mixture thereof.

In one embodiment the biodegradable polymer matrix material for thebead, foam and/or the skin layer or mesh surrounding the foam mayinclude polyglycolic acid (“PGA”), polylactic acid (“PLA”),polycaprolactic acid (“PCL”), poly-p-dioxanone (“PDO”), PGA/PLAcopolymers, PGA/PCL copolymers, PGA/PDO copolymers, PLA/PCL copolymers,PLA/PDO copolymers, PCL/PDO copolymers or combinations thereof.

In another embodiment, the biodegradable polymer matrix material mayinclude polycarbonate polyurethanes, polycarbonate urea-urethanes,polyether polyurethanes, poly(carbonate-co-ether) urea-urethanes,polysiloxanes and the like.

In one embodiment, the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix further comprising a biodegradable foamwherein the biodegradable polymer matrix comprising a biocompatible,cross-linked, biodegradable polyurethane, the matrix having acontinuous-interconnected void phase. According to an aspect, thepolyurethane degrades in a body of an animal to cause a loss of weightof the matrix and the resultant void phase is further ingrown andproliferated by tissues or biological tissue and in one embodiment,further ingrown and proliferated tissues can re-model to becomesubstantially similar to the surrounding tissue in the body of an animalwhere it was placed.

In one aspect, the polyurethane matrix comprises biodegradable,polyol-derived soft segments and isocyanate-derived hard segments.According to an aspect, the matrix has substantially non-crystallineisocyanate-derived hard segments. According to an aspect, thepolyurethane matrix is derived from an amount of glycerol sufficient toat least partially cross-link the isocyanate-derived hard segments.According to an aspect, the isocyanate-derived hard segments aresubstantially free from biuret and/or allophanate and/or isocyanurategroups.

According to an aspect, the polyurethane matrix comprises at least oneat least one auxiliary agent which may comprise glycerol, water,surfactants, cell-openers, viscosity modifiers, catalysts and solvents.

Surfactant may include but are not limited to TEGOSTAB® BF 2370 fromGoldschmidt, D.C. 5241 from Dow Corning (Midland, Mich.), polysorbate,poloxamer and other non-ionic organosilicones, such as thepolydimethylsiloxane types available from Dow Corning, Air Products andGeneral Electric (Waterford, N.Y.).

Catalysts may include but are not limited to tertiary amine catalystslike the TOTYCAT® line from Toyo Soda Co. (Japan), the TEXACAT® linefrom Texaco Chemical Co. (Austin, Tex.), the KOSMOS® and TEGO® linesfrom Th. Goldschmidt Co. (Germany), the DMP® line from Rohm and Haas(Philadelphia, Pa.), the KAO LIZER® line from Kao Corp. (Japan), and theQUINCAT® line from Enterprise Chemical Co. (Altamonte Springs, Fla.).Exemplary organotin catalysts include the FOMREZ® and FOMREZ UL® linesfrom Witco Corporation (Middlebury, Conn.), the COCURE® and COSCAT®lines from Cosan Chemical Co. (Carlstadt, N.J.), and the DABCO® andPOLYCAT® lines from Air Products.

Cell-opener may include ORTEGOL® 501 from Goldschmidt.)

The viscosity modifier propylene carbonate (from Sigma-Aldrich)

Solvents include by are not limited to: acetone, N-methylpyrrolidone(“NMP”), DMSO, toluene, methylene chloride, chloroform,1,1,2-trichloroethane (“TCE”), various freons, dioxane, ethyl acetate,THF, DMF and DMAC.

According to an aspect, the matrix comprising biocompatible,cross-linked, biodegradable polyurethane, the matrix having acontinuous-interconnected void phase, wherein said matrix is configuredto be in-grown by a biological tissue. The continuous-interconnectedvoid phase is termed as reticulated matrix and is interconnected andintercommunicating networks of cells, pores, and voids to permitingrowth and proliferation of tissue into the matrix interiors or in oneembodiment into the device interiors.

In one embodiment, the present invention relates provides biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix further comprising a biodegradable foam,wherein the device is suitable for delivery of small molecules havingmolecular weight less than 500 as well as large biologics entities likepeptides, antibodies and nucleic acid analogs such as modified RNA,small interfering RNA, anti-sense DNA or fragments thereof.

In one embodiment, the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix further comprising a biodegradable foam,wherein the device is suitable for delivery of lidocaine, diclofenec,clonidine, estradiol, estradiol/norethindrone acetate,estradiol/levonorgestrel, fentanyl, methylphenidate, nicotine,norelgestromin/ethinyl estradiol, nitroglycerin, oxybutynin,scopolamine, selegiline, testosterone, rivastigmine, rotogotine.

In one embodiment the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix further comprising a biodegradable foam,wherein the device is suitable for delivery of long-term sustainedrelease of insulin or analogs thereof, GLP-1 or analogs thereof, aloneor in combination of other therapies, to treat diabetes or othermetabolic conditions.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of long-term release of contraceptive hormones, combinationof estrogen or progestin or singular delivery of progesterone alone andserves as contraceptive aid for women.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of long-term therapeutic benefit for ocular diseases, suchas age related macular degeneration, dry eye and various others.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of any small molecule or biologic therapy to treat urinarybladder complications such as incontinence, yeast infections, bladdercancer and various others.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of therapeutic molecules to the male reproductive organs asa means to treat medical conditions such as erectile dysfunction,premature ejaculation, testicular cancer and various others pertainingto male reproductive system.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of therapeutic molecules to female reproductive organs,uterus and ovaries, to treat medical conditions such as endometriosis,uterine fibroids, ovarian cancer, uterine cancer, poly cystic ovariansyndrome, and various other diseases pertaining to female reproductivesystem.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of therapeutic molecules to heart to treat conditions suchas heart failure, myocardial ischemia, and various other heart diseases.

In one aspect of this embodiment, the biodegradable device is suitablefor delivery of therapeutic molecules into the adipose tissue to treatconditions such as metabolic syndrome, diabetes, hypercholesterolemia,hypertriglyceridemia and various others.

In another embodiment, the present invention relates to a biodegradabledevice for controlled delivery of drugs, comprising a micro or nanofluidic beads that contains drug, wherein the beads are embedded in abiodegradable polymer matrix, further comprising a biodegradable foamwherein a top coating can be applied to delay release of the activeagent. In another embodiment, a top coating can be used as the matrixfor the delivery of a second active agent. A layered coating, comprisingrespective layers of fast- and slow-hydrolyzing polymer, can be used tostage release of the active agent or to control release of differentactive agents placed in the different layers. Polymer blends may also beused to control the release rate of different active agents or toprovide a desirable balance of coating characteristics (e.g.,elasticity, toughness) and drug delivery characteristics (e.g., releaseprofile). Polymers with differing solvent solubilities can be used tobuild-up different polymer layers that may be used to deliver differentactive agents or to control the release profile of active agents.

The amount of an active agent present depends upon the particular theactive agent employed and medical condition being treated. In oneembodiment, the active agent is present in an effective amount. Inanother embodiment, the amount of the active agent represents from about0.01% to about 60% of the coating by weight. In another embodiment, theamount of the active agent represents from about 0.01% to about 40% ofthe coating by weight. In another embodiment, the amount of the activeagent represents from about 0.1% to about 20% of the coating by weight.

The drug delivery device could include a device such as amonitor/transmitter with ability to detect blood glucose levels, sensehormonal levels, and/or detect body temperature. The drug deliverydevice could include a device such as a monitor/transmitter an abilityto communicate to the sensors/detectors in smartphone, an ability totransmit data to iCloud, and/or an ability to sense appetite sensinghormones.

In one embodiment, the drug delivery device could comprise a shellcomprising a first material and a second material, wherein the secondmaterial comprises a biodegradable material; a core comprising apharmaceutically effective composition, the core being enclosed by theshell; wherein the first material is distributed in a matrix of thebiodegradable material; wherein the first material is configured tocreate holes in the shell; wherein the holes allow the pharmaceuticallyeffective composition to be released to the exterior of the shellthrough the holes. In one embodiment, the shell could be made bypolymerizing a silica-functionalized monomer to form a silica-containingbiodegradable polymer shell.

In the drug delivery device, the pharmaceutically effective compositioncould comprise a targeting material or molecule that binds to a certainorgan, object or a specific site within a body of a human or an animal.Thus, for example, even if the drug is the same but used for differentcancers, then using a targeting molecule for a particular type ofcancer, e.g., breast cancer, then the drug would bind to the cells ofthat particular type of cancer. On the other hand, if the drug isintended for ovarian cancer, then the target molecule could bespecifically one that binds to the cells of ovarian cancer. Thetargeting material or molecule could be a biomarker.

An ingredient of the pharmaceutically effective composition could be amaterial that prevents the pharmaceutically effective composition frombeing taken up by the host defense as white blood and macrophages in thehuman or animal body. Such an ingredient remains in the blood but thebody organs cannot take it up. An example of such an ingredient ispolyethylene glycol (PEG), e.g., having 200 Dalton molecular weight.

In another embodiment, the biodegradable shell could contain acontrolled release ingredient that functions as a control release sensorto control the release of the drug. For example, one would want aparticular concentration of the drug at a given site over a givenextended period of time. The control release ingredient could be amaterial that degrades faster than the remaining material of thebiodegradable shell or punches holes (pores) in biodegradable shell.

The holes in the biodegradable shell could be punched by giving externalstimuli such as sound, such as ultrasonic sound, radiation or microwaveto the drug containing beads. The external stimulus heats up thecontrolled release ingredient, thereby punching one or more holes in theshell surrounding the controlled release ingredient, which could be ametal-containing material is configured to form holes in the shell,before or after implanting or attaching the device in or on a body of ahuman or an animal, when the shell is exposed to an external stimulus.For example, the controlled release ingredient that can be used forpunching holes in the shell could be molecular iron such a magneticresonance imaging (MRI) contrast agent. Depending on the concentrationof the controlled release ingredient, one can control the number ofholes punched in the shell, which in turn controls the amount of drugreleased from the core to the outside of the shell.

Two types of iron oxide MRI contrast agents exist: superparamagneticiron oxide (SPIO) and ultrasmall superparamagnetic iron oxide (USPIO).These contrast agents consist of suspended colloids of iron oxidenanoparticles. A FDA approved iron oxide MRI contrast is Lumirem (alsoknown as Gastromark).

Other controlled release ingredients for punching holes in the shellcould be superparamagnetic iron platinum particles (SIPPs). SIPPs couldalso encapsulated with phospholipids to create multifunctional SIPPstealth immunomicelles that specifically targeted human prostate cancercells.

Yet, other controlled release ingredients for punching holes in theshell are Mn-based nanoparticles. Manganese ions (Mn2+) are often usedas a contrast agent in animal studies, usually referred to as MEMRI(Manganese Enhanced MRI). For example, Mn2+ carbon nanostructurecomplexes of graphene oxide nanoplatelets and graphene oxide nanoribbonscould also be used as controlled release ingredients.

Uses Thereof:

Use of such device for systemic delivery any active pharmaceuticalingredient in humans or animals, as a patient convenience to avoiddaily, weekly or monthly oral, subcutaneous or intravenousadministration.

Use of such device for systemic delivery any biologic therapy in humansor animals as a means of patient convenience to overcome daily, weeklyor monthly oral, subcutaneous or monthly administration. Biologicmolecules can be peptides, antibodies or fragments thereof, nucleic acidmolecules such as modified RNA, small interfering RNA, anti-sense DNAmolecules or fragments thereof.

Use of such device to deliver antigens to elicit vaccine responses inhumans or animals.

Use of such device to provide local tissue delivery of any therapeuticmolecule, be it small molecule or biologic.

Use of such device to provide long-term sustained release of insulin oranalogs thereof, alone or in combination of other therapies, to treatdiabetes or other metabolic conditions.

Use of such device to provide long-term sustained release of GLP-1 oranalogs thereof, alone or in combination of other therapies, to treatdiabetes or other metabolic conditions.

Deposition of such device underneath the skin, or in fat tissue or inany specific organ for the purpose of long-term release of anytherapeutic molecule, be it either a small molecule or biologic.

Specific use of such device to provide sustained long-term release ofcontraceptive hormones, combination of estrogen or progestin or singulardelivery of progesterone alone and serve as contraceptive aid for women.

Specific use of such device for the intraocular delivery of any smallmolecule or biologic therapy as a means to provide the long-termtherapeutic benefit for ocular diseases, such as age related maculardegeneration, dry eye and various others.

Deposition of such device and use to directly into bladder for long-termdelivery of any small molecule or biologic therapy to treat urinarybladder complications such as incontinence, yeast infections, bladdercancer and various others.

Deposition of such device and use to locally deliver therapeuticmolecules to the male reproductive organs as a means to treat medicalconditions such as erectile dysfunction, premature ejaculation,testicular cancer and various others pertaining to male reproductivesystem.

Deposition of such device and use to locally deliver therapeuticmolecules to female reproductive organs, uterus and ovaries, to treatmedical conditions such as endometriosis, uterine fibroids, ovariancancer, uterine cancer, poly cystic ovarian syndrome, and various otherdisease pertaining to female reproductive system.

Deposition of such device and use to locally deliver therapeuticmolecules to heart to treat conditions such as heart failure, myocardialischemia, and various other heart diseases.

Deposition of such device and use to locally deliver therapeuticmolecules into the adipose tissue to treat conditions such as metabolicsyndrome, diabetes, hypercholesterolemia, hypertriglyceridemia andvarious others.

The advantages of the present invention will become readily apparent bythose skilled in the art from the following detailed description,wherein it is shown and described preferred embodiments of theinvention, simply by way of illustration of the best mode contemplatedof carrying out the invention. As will be realized the invention iscapable of other and different embodiments, and its several details arecapable of modifications in various obvious respects, without departingfrom the invention. Accordingly, the description is to be regarded asillustrative in nature and not as restrictive.

INCORPORATION BY REFERENCE

All patents, application and publications referred to in thisapplication are incorporated herein by reference in their entirety.

The invention claimed is:
 1. A drug delivery product comprisingsustained release particles, each sustained release particle comprisinga shell and a core, wherein the shell comprises a first material and asecond material, the second material comprising a first biodegradablematerial, wherein the core is enclosed by the shell and the corecomprises a drug, wherein the first material is distributed in a matrixof the first biodegradable material, wherein the first material isconfigured to create holes in the shell and is selected from metallicparticles, and wherein the holes allow the drug to be released to theexterior of the shell through the holes, the drug delivery productfurther comprising: an inner region, wherein the sustained releaseparticles are enclosed in the inner region, and a skin or barrier layerat least partially surrounding the inner region; wherein the drugdelivery product is substantially biodegradable when the drug deliveryproduct is implanted within a body of a human or an animal such that thedrug delivery product does not have to be removed from the body and issubstantially biodegraded in the body, and wherein the skin or barrierlayer controls the flow of the drug from the drug delivery product to aregion outside of the drug delivery product such that the drug deliveryproduct when implanted within the body provides a controlled delivery ofthe drug into the body.
 2. The drug delivery product of claim 1, furthercomprises a second biodegradable material that biodegrades faster thanthe first biodegradable material over time.
 3. The drug delivery productof claim 1, wherein the metallic particles comprise iron-containing ormanganese-containing particles, or an iron-containing ormanganese-containing polymer.
 4. The drug delivery product of claim 1,wherein the drug comprises a targeting material or targeting moleculethat binds to a certain organ, object or a specific site within a bodyof a human or an animal.
 5. The drug delivery product of claim 1,wherein the first and second materials comprise polymers.
 6. The drugdelivery product of claim 1, wherein the first material comprises polylactic acid (PLA) or an iron-containing polymer and the second materialcomprises poly ε-caprolactone (PCL).
 7. The drug delivery product ofclaim 1, wherein the core comprises an emulsion of the drug and apolymer.
 8. The drug delivery product of claim 1, wherein the corecomprises drug containing beads.
 9. The drug delivery product of claim1, wherein the sustained release particles comprise beads, each beadcomprising the shell and the core.
 10. The drug delivery product ofclaim 1, wherein the drug delivery product is an implantable drugdelivery device.
 11. The drug delivery product of claim 1, wherein thesustained release particles are embedded in a biodegradable polymermatrix or a biodegradable foam.
 12. The drug delivery product of claim11, wherein the biodegradable polymer matrix or the biodegradable foamcomprises a biodegradable sol-gel or a biodegradable thermoplasticpolymer.
 13. The drug delivery product of claim 11, wherein the skin orbarrier layer comprises a third biodegradable material.
 14. The drugdelivery product of claim 13, wherein the first, second and thirdbiodegradable materials have different compositions.
 15. The drugdelivery product of claim 13, wherein a time for biodegradability of thesustained release particles is shorter than a time for biodegradabilityof the biodegradable polymer matrix or the biodegradable foam in whichthe sustained release particles are embedded, and the time forbiodegradability of the biodegradable polymer matrix or thebiodegradable foam is shorter than a time for biodegradability of theskin or barrier layer surrounding the biodegradable polymer matrix orthe biodegradable foam.
 16. The drug delivery product of claim 1,wherein the metallic particles are configured to form holes in theshell, before or after implanting or attaching the drug delivery productin or on a body of a human or an animal, when the shell is exposed to anexternal stimulus.
 17. The drug delivery product of claim 1, wherein themetallic particles comprise an iron-containing polymer.
 18. The drugdelivery product of claim 1, wherein the metallic particles comprisemolecular iron or iron platinum particles.
 19. The drug delivery productof claim 18, wherein the molecular iron comprises iron oxide.